Ceftriaxone associated with threefold mortality increase in MSSA bloodstream infections: implications for OPAT prescribing

Maraolo et al. (Annals of Medicine 58(1):2667672; PMID 42112603) conducted a systematic review and meta-analysis of 11 studies totalling 2,568 patients comparing ceftriaxone with antistaphylococcal penicillins or cefazolin for methicillin-susceptible Staphylococcus aureus bloodstream infections (MSSA-BSI). Ceftriaxone was associated with significantly increased 30-day mortality: odds ratio 3.33 (95% CI 2.17–5.10). The difference at 90 days was not statistically significant (OR 1.71; 95% CI 0.75–3.90). No significant differences were observed in clinical success or microbiological clearance. Adverse event rates were similar between groups. The protocol was prospectively registered (PROSPERO CRD42024595748) and the search covered PubMed, Embase, and Scopus to December 2025.

This finding carries direct implications for outpatient parenteral antimicrobial therapy (OPAT) services. Ceftriaxone is the most widely used OPAT antibiotic, favoured for its once-daily dosing and ease of community administration. However, this meta-analysis demonstrates that for confirmed MSSA bacteraemia — one of the most common indications for prolonged intravenous antibiotics — the convenience of ceftriaxone comes at a measurable mortality cost. The authors conclude that routine use of ceftriaxone for MSSA-BSI, especially as initial therapy, is not supported by current evidence, and that only novel findings from randomised studies may change its place in therapy.

A concurrent Norwegian cost analysis provides the practical pathway to safer prescribing. Helleren et al. (JAC-Antimicrobial Resistance 8(3):dlag052; PMID 42100600) evaluated 170 consecutive patients treated with OPAT using continuous ambulatory delivery device (CADD) pumps at Sørlandet Hospital, Norway, between 2016 and 2021. The mean cost per OPAT episode was €1,603 versus €12,982 for inpatient care — an 88% saving, confirmed between 72% and 89% across sensitivity analyses. The programme saved approximately 51 hospital bed-days per month, with a mean treatment duration of 16.4 days per patient (range 1–67 days). Most patients received narrow-spectrum beta-lactam antibiotics — the very class of drugs (antistaphylococcal penicillins) that the Maraolo meta-analysis identifies as safer alternatives to ceftriaxone for MSSA-BSI.

The interaction between these two studies defines a clear direction for OPAT service design. The mortality signal against ceftriaxone does not argue against community-based intravenous antibiotic delivery; it argues for investment in infusion pump infrastructure that can deliver safer antibiotics in the home setting. CADD-pump or elastomeric device platforms support continuous or multiple-daily-dose delivery of flucloxacillin or other antistaphylococcal penicillins — agents with established efficacy for MSSA-BSI that cannot be delivered as a once-daily gravity infusion. Services that currently rely on ceftriaxone as their default OPAT agent for staphylococcal bacteraemia should review prescribing practice in light of this meta-analysis and assess the feasibility of pump-based delivery for confirmed MSSA-BSI cases. The Helleren data demonstrate that such a shift is not only clinically safer but economically favourable: CADD-pump OPAT costs 12% of inpatient care while supporting antimicrobial stewardship through narrower-spectrum prescribing.